417 research outputs found
Contrasting perspectives on China's rare earths policies: Reframing the debate through a stakeholder lens
Delta isobar masses, large N_c relations, and the quark model
Motivated by recent remarks on the Delta+ mass and comparisons between the
quark model and relations based on large-N_c with perturbative flavor breaking,
two sets of Delta masses consistent with these constraints are constructed.
These two sets, based either on an experimentally determined mass splitting or
a quark model of isospin symmetry breaking, are shown to be inconsistent. The
model dependence of this inconsistency is examined, and suggestions for
improved experiments are made. An explicit quark model calculation and mass
relations based on the large-N_c limit with perturbative flavor breaking are
compared. The expected level of accuracy of such relations is realized in the
quark model, except for mass relations spanning more than one SU(6)
representation. It is shown that the Delta0 and Delta++ pole masses and Delta0
- Delta+ = (Delta- - Delta++)/3 about 1.5 MeV are more consistent with model
expectations than the analogous Breit-Wigner masses and their splittings.Comment: 10 pages, including 1 eps figure, revte
An updated analysis of NN elastic scattering data to 1.6 GeV
An energy-dependent and set of single-energy partial-wave analyses of
elastic scattering data have been completed. The fit to 1.6~GeV has been
supplemented with a low-energy analysis to 400 MeV. Using the low-energy fit,
we study the sensitivity of our analysis to the choice of coupling
constant. We also comment on the possibility of fitting data alone. These
results are compared with those found in the recent Nijmegen analyses. (Figures
may be obtained from the authors upon request.)Comment: 17 pages of text, VPI-CAPS-7/
Nucleon-nucleon elastic scattering analysis to 2.5 GeV
A partial-wave analysis of NN elastic scattering data has been completed.
This analysis covers an expanded energy range, from threshold to a laboratory
kinetic energy of 2.5 GeV, in order to include recent elastic pp scattering
data from the EDDA collaboration. The results of both single-energy and
energy-dependent analyses are described.Comment: 23 pages of text. Postscript files for the figures are available from
ftp://clsaid.phys.vt.edu/pub/said/n
Charge and lipophilicity are required for effective block of the hair-cell mechano-electrical transducer channel by FM1-43 and its derivatives
The styryl dye FM1-43 is widely used to study endocytosis but behaves as a permeant blocker of the mechano-electrical transducer (MET) channel in sensory hair cells, loading rapidly and specifically into the cytoplasm of hair cells in a MET channel-dependent manner. Patch clamp recordings of mouse outer hair cells (OHCs) were used to determine how a series of structural modifications of FM1-43 affect MET channel block. Fluorescence microscopy was used to assess how the modifications influence hair-cell loading in mouse cochlear cultures and zebrafish neuromasts. Cochlear cultures were also used to evaluate otoprotective potential of the modified FM1-43 derivatives. Structure-activity relationships reveal that the lipophilic tail and the cationic head group of FM1-43 are both required for MET channel block in mouse cochlear OHCs; neither moiety alone is sufficient. The extent of MET channel block is augmented by increasing the lipophilicity/bulkiness of the tail, by reducing the number of positive charges in the head group from two to one, or by increasing the distance between the two charged head groups. Loading assays with zebrafish neuromasts and mouse cochlear cultures are broadly in accordance with these observations but reveal a loss of hair-cell specific labelling with increasing lipophilicity. Although FM1-43 and many of its derivatives are generally cytotoxic when tested on cochlear cultures in the presence of an equimolar concentration of the ototoxic antibiotic gentamicin (5 µM), at a 10-fold lower concentration (0.5 µM), two of the derivatives protect OHCs from cell death caused by 48 h-exposure to 5 µM gentamicin
Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.
Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.The work was supported by grants from Cancer Research UK (ref. C309/A11566, ref. C309/A8274 and ref. C309/A8992 (PW), ref. C423/A1421 and ref. C423/A15043 (SM)) and the World Cancer Research Fund (WCRF) (ref. 12-1280). CZ was supported by a Wellcome Trust studentship (ref. 094885/Z/10/Z)
Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein
BACKGROUND: Patients with antibody deficiency respond poorly to COVID-19 vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesised that immunoglobulin preparations will now contain neutralising SARS-CoV-2 spike antibodies which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralising capacity of patient samples and immunoglobulin products was assessed using in vitro pseudo-virus and live-virus neutralisation assays, the latter investigating multiple batches against current circulating omicron variants. We describe the clinical course of nine patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titre increased from 2123 to 10600 U/ml post-infusion, with corresponding increase in pseudo-virus neutralisation titres to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralisation, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside Remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum over 900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 virus at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralising anti-SARS-CoV-2 antibodies which are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity
Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.
Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.The work was supported by grants from Cancer Research UK (ref. C309/A11566, ref. C309/A8274 and ref. C309/A8992 (PW), ref. C423/A1421 and ref. C423/A15043 (SM)) and the World Cancer Research Fund (WCRF) (ref. 12-1280). CZ was supported by a Wellcome Trust studentship (ref. 094885/Z/10/Z)
- …